Fetal Pb-exposure and Neurodegeneration in Aging Brains

Riyaz MahammadDepartment of Biomedical Sciences; University of Rhode Island

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The hallmark pathological features of AD (amyloid plaques and associated proteins) are present in normal aging indivduals suggesting that AD may result from the acceleration of normal age-related processes in the brain. The sporadic nature of most AD cases strongly argues for a role for an environmental link that may drive AD pathogenesis; however, it is not clear when this may occur. Therefore it is important to identify environmental triggers and to pinpoint the period during which such factors pose the greatest risk. Recently, we have reported that developmental exposure of rats to the xenobiotic metal lead (Pb) resulted in a delayed over-expression (20 months later) in the amyloid precursor protein (APP) and its amyloidogenic Ab product (Basha et al., 2005). These findings suggested that environmental influences occurring during brain development pre-determine the expression and regulation of APP later in life, potentially influencing the course of amyloidogenesis. In order to link these molecular perturbations to possible pathological consequences associated with AD, we have acquired the brains of monkeys who have been similarly exposed to Pb as infants in the 1980's. Primates are among the few animal models that express amyloid plaques and other AD pathological features that are absent in normal non-transgenic rodents. Preliminary experiments in tissue derived from these primates demonstrate that the APP mRNA, APP, and Ab are elevated in old monkeys developmentally-exposed to Pb. Immunohistochemical staining for Ab showed that early exposure to Pb altered the distribution of intracellular Ab staining and plaques formation. Furthermore, we found that the activity of the selective DNA methyltransferase was significantly decreased in these old monkeys, suggesting that alterations in epigenetic control of gene expression had occurred in the exposed animals. Our current FeBAD grants supports lifespan studies with mice in order to develop a baseline for molecular and pathological changes due to various developmental exposure scenarios and allow us to extend our studies to a very late period in life as well as permit the utilization of APP transgenic mice for future work.